WO2020086616A1 - Tyk2 inhibitors and uses thereof - Google Patents

Tyk2 inhibitors and uses thereof Download PDF

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Publication number
WO2020086616A1
WO2020086616A1 PCT/US2019/057485 US2019057485W WO2020086616A1 WO 2020086616 A1 WO2020086616 A1 WO 2020086616A1 US 2019057485 W US2019057485 W US 2019057485W WO 2020086616 A1 WO2020086616 A1 WO 2020086616A1
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WIPO (PCT)
Prior art keywords
alkyl
haloalkyl
heterocycloalkyl
cycloalkyl
heteroaryl
Prior art date
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PCT/US2019/057485
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English (en)
French (fr)
Inventor
Bohan Jin
Qing Dong
Gene Hung
Stephen W. Kaldor
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Fronthera U.S. Pharmaceuticals Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR112021007679-4A priority Critical patent/BR112021007679A2/pt
Priority to MX2021004538A priority patent/MX2021004538A/es
Application filed by Fronthera U.S. Pharmaceuticals Llc filed Critical Fronthera U.S. Pharmaceuticals Llc
Priority to KR1020217015306A priority patent/KR20210095634A/ko
Priority to CN201980084885.9A priority patent/CN113490664A/zh
Priority to CA3117200A priority patent/CA3117200A1/en
Priority to AU2019364336A priority patent/AU2019364336B2/en
Priority to EP19877015.8A priority patent/EP3870579A4/en
Priority to JP2021523157A priority patent/JP2022505987A/ja
Priority to SG11202104017VA priority patent/SG11202104017VA/en
Publication of WO2020086616A1 publication Critical patent/WO2020086616A1/en
Priority to US16/938,183 priority patent/US11053219B2/en
Priority to IL282487A priority patent/IL282487A/en
Priority to US17/243,508 priority patent/US12006306B2/en
Priority to US17/713,646 priority patent/US20220235035A1/en
Priority to US17/891,817 priority patent/US11731956B2/en
Priority to US18/335,262 priority patent/US20230391751A1/en

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Definitions

  • Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds for inhibiting nonreceptor tyrosine-protein kinase 2 (“TYK2”), also known as Tyrosine kinase 2.
  • TYK2 nonreceptor tyrosine-protein kinase 2
  • TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases.
  • the mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling.
  • TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g.
  • IFN-a, IFN-b, IFN-k, IFN-d, IFN-e, IFN-t, IFN-w, and IFN-z also known as limitin
  • interleukins e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF.
  • the activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.
  • TYK2 activation by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis.
  • IBD inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis A genome-wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2.
  • Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis.
  • TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis.
  • COPD chronic obstructive pulmonary disease
  • GCH Goblet cell hyperplasia
  • mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.
  • TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis.
  • decreased Tyk2 activity reduced the production of Th1/Th17-related cytokines and matrix metalloproteases, and other key markers of inflammation.
  • EAE encephalomyelitis
  • MS multiple sclerosis
  • TYK2 is the sole signaling messenger common to both IL-12 and IL-23.
  • TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.
  • TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.
  • T-ALL T-cell acute lymphoblastic leukemia
  • TYK2 T-cell acute lymphoblastic leukemia
  • STAT1 STAT1 -mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2.
  • Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V73 II), and the kinase domain (E957D and R1027H).
  • TYK2 kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) resulted in failure to transform.
  • TYK2 has been suggested as a suitable target for patients with IL- 10 and/or BCL2 -addicted tumors, such as 70% of adult T-cell leukemia cases.
  • TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-b (Ab) peptide.
  • compounds that inhibit the activity of TYK2 are beneficial, especially those with selectivity over JAK2.
  • Such compounds should deliver a pharmacological response that favorably treats one or more of the conditions described herein without the side-effects associated with the inhibition of JAK2.
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • composition comprising a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of inhibiting a TYK2 enzyme in a patient or biological sample comprising contacting said patient or biological sample with a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • a method of treating a TYK2-mediated disorder comprising administering to a patient in need thereof a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.
  • the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling.
  • “Aliphatic chain” refers to a linear chemical moiety that is composed of only carbons and hydrogens.
  • the aliphatic chain is saturated.
  • the aliphatic chain is unsaturated.
  • the unsaturated aliphatic chain contains one unsaturation.
  • the unsaturated aliphatic chain contains more than one unsaturation.
  • the unsaturated aliphatic chain contains two unsaturations.
  • the unsaturated aliphatic chain contains one double bond. In some embodiments, the unsaturated aliphatic chain contains two double bonds.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1- propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-buty
  • a numerical range such as“C 1 -C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl.
  • an alkyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as“C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkenyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched- chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as“C 2 -C 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkynyl is optionally substituted with oxo, halogen, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkynyl is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined.
  • an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an alkoxy is optionally substituted with oxo, halogen, -CN, -CF 3 , -OH, or -OMe.
  • the alkoxy is optionally substituted with halogen.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Deuteroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atomss. Deuteroalkyl includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuteroalkyl is CD 3 .
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with one, two, or three halogen atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six halogen halogens.
  • Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.
  • Halo or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl examples include, for example, -CH 2 OCH 3 , - CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , or -CH(CH 3 )OCH 3 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, - CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Hydroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example,
  • hydroxymethyl hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl.
  • the hydroxyalkyl is hydroxymethyl.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. In some embodiments, the heterocycloalkyl comprises 1 or 2 heteroatoms selected from nitrogen and oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl).
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl.
  • the cycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholiny
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to, the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heterocycloalkyl is optionally substituted with halogen.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl.
  • a Heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the heteroaryl is optionally substituted with halogen.
  • the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease.
  • “treatment,”“prevention,” “amelioration,” or“inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • an“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • an appropriate“effective” amount in any individual case is determined using techniques, such as a dose escalation study.
  • TYK2 -mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role.
  • TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.
  • the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • each R Z is independently hydrogen, deuterium, halogen, -CN, -OR b , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • the compound is of Formula (Ia):
  • the compound is of Formula (Ib):
  • R 3 is hydrogen or
  • R 3 is hydrogen.
  • Z is a bond or -CH 2 -. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Z is -CH 2 -. In some embodiments of a compound of Formula (I), (Ia), or (Ib), Z is a bond.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 1 is hydrogen. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (I), (Ia), or (Ib), R 2 is C 1 -C 6 deuteroalkyl.
  • R 7 is C 1 -C 6 alkyl
  • R 7 is unsubstituted cycloalkyl.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (II) or (II’), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II) or (II’), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (II) or (II’), X is -N-.
  • the compound is of Formula (IIa) or (II’a):
  • the compound is of Formula (IIb) or (II’b):
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (II), (II’), (IIa), (II’a), (IIb), or (II’b), R 3 is hydrogen.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl.
  • R 1 is hydrogen.
  • R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl.
  • R 2 is C 1 -C 6 deuteroalkyl.
  • R 7 is unsubstituted cycloalkyl.
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl,
  • R 11 is deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R 11 is halogen.
  • R 11 is hydrogen.
  • Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; provided that is not
  • n 0-4;
  • each Y is independently C or N;
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (III), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (III), X is -N-.
  • the compound is of Formula (IIIa):
  • the compound is of Formula (IIIb):
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), R 3 is hydrogen.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloal
  • R 7 is unsubstituted cycloalkyl.
  • Ring B is a heterocycloalkyl or heteroaryl.
  • each R B is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl; two R B on the same carbon are taken together to form an oxo.
  • n is 0. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0-2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 0 or 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1 or 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n is 1-3.
  • n’ is 0. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n’ is 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n’ is 2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n’ is 0-2. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n’ is 0 or 1. In some embodiments of a compound of Formula (III), (IIIa), or (IIIb), n’ is 1 or 2.
  • Ring C is a bicyclic ring system
  • n 0-4;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • L 1 is -O-, -NH-, or -N(CH 3 )-;
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IV), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (IV), X is -N-.
  • the compound is of Formula (IVa):
  • the compound is of Formula (IVb):
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 1 is hydrogen. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), R 2 is C 1 -C 6 deuteroalkyl.
  • L 1 is -NH-. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), L 1 is -O- or -NH-.
  • R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloal
  • R 7 is unsubstituted cycloalkyl.
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, cycloalkyl, heterocycloalkyl,
  • Ring C is indole or benzimidazole.
  • each R C is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), each R C is independently halogen or C 1 -C 6 alkyl.
  • m is 0. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 0 or 1. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 0-2. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 1 or 2. In some embodiments of a compound of Formula (IV), (IVa), or (IVb), m is 1-3.
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • r 0-4;
  • each Y is independently C or N;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • each X is -N-.
  • each X is -CH-.
  • one X is -N- and the other is -CH-.
  • the compound is of Formula (Va):
  • the compound is of Formula (Vb):
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 3 is hydrogen.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 1 is hydrogen. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), R 2 is C 1 -C 6 deuteroalkyl.
  • Ring D is a
  • heterocycloalkyl or heteroaryl are heterocycloalkyl or heteroaryl.
  • each R D is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl. In some embodiments of a compound of Formula (V), (Va), or (Vb), each R D is independently hydrogen or cycloalkyl.
  • r is 0. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 0-2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 0 or 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1 or 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r is 1-3.
  • r’ is 0. In some embodiments of a compound of Formula (V), (Va), or (Vb), r’ is 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r’ is 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r’ is 0-2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r’ is 0 or 1. In some embodiments of a compound of Formula (V), (Va), or (Vb), r’ is 1 or 2. In some embodiments of a compound of Formula (V), (Va), or (Vb), r’ is 1-3.
  • Ring E is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R E ;
  • L 2 is a bond, -O-, or
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (VI), X is -N-.
  • the compound is of Formula (VIa):
  • the compound is of Formula (VIb):
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 3 is hydrogen.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 1 is hydrogen. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VI), (VIa), or (VIb), R 2 is C 1 -C 6 deuteroalkyl.
  • L 2 is a bond.
  • Ring E is cycloalkyl, heterocycloalkyl, or aryl; each optionally substituted with one or more R E .
  • Ring E is aryl optionally substituted with one or more R E .
  • each R E is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • each R E is independently halogen.
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VII), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VII), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (VII), X is -N-.
  • the compound is of Formula (VIIb):
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 3 is hydrogen.
  • R 7 is unsubstituted cycloalkyl.
  • R 9 and R 10 are independently hydrogen,
  • R 14 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or C 1 -C 6 alkyl(cycloalkyl). In some embodiments of a compound of Formula (VII), (VIIa), or (VIIb), R 14 is C 1 -C 6 alkyl or C 1 -C 6 alkyl(cycloalkyl).
  • L 3 is -O-, -NH-, or -N(CH 3 )-;
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (VIII), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VIII), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (VIII), X is -N-.
  • R 7 is unsubstituted cycloalkyl.
  • R 9 and R 10 are independently hydrogen,
  • L 3 is -O-. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), L 3 is -NH-.
  • R 15 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, or cycloalkyl.
  • L 4 is -NR 3 -.
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (VIII), (VIIIa), or (VIIIb), R 3 is hydrogen.
  • Ring F is a heterocycloalkyl or heteroaryl
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (IX), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IX), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (IX), X is -N-.
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), R 3 is hydrogen.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloal
  • R 7 is unsubstituted cycloalkyl.
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, aryl, or heteroaryl; wherein each alkyl
  • Ring F is a heterocycloalkyl.
  • each R F is
  • each R F is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • p is 0. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 0. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 1. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 0-2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 0 or 1. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 1 or 2. In some embodiments of a compound of Formula (IX), (IXa), or (IXb), p is 1-3.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • L 1 is -O-, -NH-, or -N(CH 3 )-;
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • X is -CR x - or -N-;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (X), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (X), X is -N-.
  • the compound is of
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 3 is hydrogen.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 1 and R 2 are independently hydrogen or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 1 is hydrogen.
  • R 2 is C 1 -C 6 alkyl or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), R 2 is C 1 -C 6 deuteroalkyl.
  • R 12 is -L 1 - R 13 .
  • L 1 is - NH-. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 1 is -O- or - NH-.
  • R 13 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl.
  • L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L5 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-.
  • L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L5 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with - NH- or -O-.
  • L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L5 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-.
  • L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L5 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb-1), L 5 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • each R L5 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (X), (Xa), (Xa-1), (Xb), or (Xb- 1), each R L5 is independently deuterium or halogen.
  • L 5 is .
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • X is -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XI), each R A is independently C 1 -C 6 alkyl.
  • R 4 is hydrogen or -OR b .
  • R 4 is -OR b .
  • R 4 is hydrogen.
  • X is -CH-. In some embodiments of a compound of Formula (XI), X is -N-.
  • R 3 is hydrogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), R 3 is hydrogen.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloal
  • R 7 is unsubstituted cycloalkyl.
  • L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-.
  • L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-.
  • L 6 is a saturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-.
  • L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms optionally substituted with one or more R L6 , wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH-, -N(CH 3 )-, or -O-. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), L 6 is an unsaturated linear aliphatic chain having 1-8 carbon atoms, wherein 1, 2, or 3 carbon atoms are optionally replaced with -NH- or -O-.
  • each R L6 is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XI), (XIa), or (XIb), each R L6 is independently deuterium or halogen.
  • L 6 is .
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring B is cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • each X is independently -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 11a ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is aryl. In some embodiments of a compound of Formula (XII), Ring B is phenyl. In some embodiments of a compound of Formula (XII), Ring B is heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is 5- or 6-membered heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is 6-membered heteroaryl. In some embodiments of a compound of Formula (XII), Ring B is pyridyl.
  • R 1 and R 2 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;
  • R 3 and R 4 are taken together to form an optionally substituted ring
  • Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R A ;
  • each X is independently -CR x - or -N-;
  • R x and R 5 are taken together to form ring D optionally substituted with one or more R D ;
  • Ring D is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
  • each R 8 is independently hydrogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R 9 and R 10 are taken together with the nitrogen atom to which they are attached to form a
  • R 11 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalky
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl,
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl,
  • R c and R d are taken together with the nitrogen atom to which they are attached to form a
  • -L-Ring A is absent.
  • Ring A is heterocycloalkyl or heteroaryl; each optionally substituted with one or more R A .
  • Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; each optionally substituted with one or more R A .
  • Ring A is heteroaryl optionally substituted with one or more R A .
  • each R A is independently deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl. In some embodiments of a compound of Formula (XII) or (XII’), each R A is independently halogen or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (XII) or (XII’), each R A is independently C 1 -C 6 alkyl.
  • each X is -N-. In some embodiments of a compound of Formula (XII), (XII’), (XIIa), (XIIb), or (XIIc) each X is -CR X -. In some embodiments of a compound of Formula (XII), (XII’), (XIIa), (XIIb), or (XIIc), two X are -N- and the other is -CR X -.
  • one X is -N- and the others are -CR X -.
  • each X is -CH-.
  • two X are -N- and the other is -CH-.
  • one X is -N- and the others are -CH-.
  • a compound of Formula (XII), (XII’), (XIIa), (XIIb), or (XIIc) is a compound of Formula (XII), (XII’), (XIIa), (XIIb), or (XIIc), (

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JP2021523157A JP2022505987A (ja) 2018-10-22 2019-10-22 Ｔｙｋ２阻害剤およびその使用
KR1020217015306A KR20210095634A (ko) 2018-10-22 2019-10-22 Tyk2 억제제 및 이의 용도
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CA3117200A CA3117200A1 (en) 2018-10-22 2019-10-22 Tyk2 inhibitors and uses thereof
AU2019364336A AU2019364336B2 (en) 2018-10-22 2019-10-22 TYK2 inhibitors and uses thereof
EP19877015.8A EP3870579A4 (en) 2018-10-22 2019-10-22 TYK2 INHIBITORS AND THEIR USES
BR112021007679-4A BR112021007679A2 (pt) 2018-10-22 2019-10-22 inibidores de tyk2 e seus usos
CN201980084885.9A CN113490664A (zh) 2018-10-22 2019-10-22 Tyk2抑制剂和其用途
US16/938,183 US11053219B2 (en) 2018-10-22 2020-07-24 Substituted pyridines as TYK2 inhibitors
IL282487A IL282487A (en) 2018-10-22 2021-04-20 TYK2 inhibitors and their use
US17/243,508 US12006306B2 (en) 2021-04-28 Substituted pyridazines as TYK2 inhibitors
US17/713,646 US20220235035A1 (en) 2018-10-22 2022-04-05 Tyk2 inhibitors and uses thereof
US17/891,817 US11731956B2 (en) 2018-10-22 2022-08-19 Substituted 1,2,4-triazoles as intermediates in the synthesis of TYK2 inhibitors
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Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021011513A1 (en) * 2019-07-16 2021-01-21 Bristol-Myers Squibb Company Prodrugs in the modulation of interleukin
CN112920103A (zh) * 2021-03-02 2021-06-08 康化（上海）新药研发有限公司 一种温和制备2-氮杂螺[3.3]庚烷盐酸盐的方法
US11053219B2 (en) 2018-10-22 2021-07-06 Esker Therapeutics, Inc. Substituted pyridines as TYK2 inhibitors
WO2021180072A1 (en) * 2020-03-11 2021-09-16 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compounds for inhibiting tyk2 activities
WO2021202652A1 (en) * 2020-04-01 2021-10-07 Eternity Bioscience Inc. Tyrosine kinase 2 inhibitors, preparation methods and medicinal uses thereof
WO2021211741A1 (en) * 2020-04-14 2021-10-21 Gossamer Bio Services, Inc. Substituted pyridines for the treatment of inflammatory diseases
CN113735836A (zh) * 2020-05-28 2021-12-03 江苏先声药业有限公司 哒嗪类化合物及其应用
CN113735837A (zh) * 2020-05-28 2021-12-03 江苏先声药业有限公司 哒嗪类化合物及其用途
CN113773262A (zh) * 2020-06-09 2021-12-10 江苏先声药业有限公司 哒嗪类化合物
WO2021259208A1 (en) * 2020-06-22 2021-12-30 Beigene, Ltd. Tyk-2 inhibitor
WO2022032484A1 (zh) * 2020-08-11 2022-02-17 北京诺诚健华医药科技有限公司 哒嗪-3-甲酰胺类化合物、其制备方法及其在医药学上的应用
WO2022033544A1 (zh) * 2020-08-13 2022-02-17 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2022105771A1 (zh) * 2020-11-17 2022-05-27 江苏恒瑞医药股份有限公司 含氮杂环类衍生物、其制备方法及其在医药上的应用
WO2022117016A1 (zh) * 2020-12-02 2022-06-09 深圳微芯生物科技股份有限公司 羟肟酸酯化合物、其制备方法及其应用
WO2022121868A1 (zh) * 2020-12-08 2022-06-16 正大天晴药业集团股份有限公司 含酰胺基和杂环烷基的tyk2抑制剂化合物
WO2022135430A1 (en) * 2020-12-22 2022-06-30 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof
WO2022179578A1 (zh) * 2021-02-24 2022-09-01 南京明德新药研发有限公司 含有亚磺酰基吡啶结构的化合物以及应用
WO2022193499A1 (en) * 2021-03-16 2022-09-22 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Amino heteroaryl compounds and compositions
WO2022213980A1 (zh) * 2021-04-07 2022-10-13 上海齐鲁制药研究中心有限公司 Tyk2抑制剂及其用途
CN115197196A (zh) * 2021-04-06 2022-10-18 扬子江药业集团有限公司 Tyk2抑制剂及其用途
WO2022233286A1 (zh) * 2021-05-04 2022-11-10 上海喆邺生物科技有限公司 一类含氮杂环吡啶类化合物
WO2022241174A1 (en) 2021-05-14 2022-11-17 Bristol-Myers Squibb Company Substituted heterocyclic compounds
WO2022253335A1 (zh) * 2021-06-02 2022-12-08 南京明德新药研发有限公司 含磺酰基的芳基类化合物及其应用
WO2022253333A1 (zh) * 2021-06-02 2022-12-08 南京明德新药研发有限公司 酰胺类化合物及其应用
WO2022268119A1 (zh) * 2021-06-22 2022-12-29 南京明德新药研发有限公司 亚磺酰亚胺类化合物及其应用
WO2023284869A1 (zh) * 2021-07-15 2023-01-19 南京明德新药研发有限公司 含硫/磷的芳基类化合物及其应用
WO2023030335A1 (zh) * 2021-08-31 2023-03-09 浙江文达医药科技有限公司 作为tyk2/jak1假激酶结构域抑制剂的化合物及合成和使用方法
WO2023054549A1 (ja) * 2021-09-30 2023-04-06 あすか製薬株式会社 分解誘導剤
WO2023064223A1 (en) * 2021-10-11 2023-04-20 Gossamer Bio Services, Inc. Tri-substituted pyridines
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
CN116284040A (zh) * 2023-01-05 2023-06-23 华润医药研究院（深圳）有限公司 含氮杂环类化合物及其医药用途
WO2023116748A1 (zh) * 2021-12-23 2023-06-29 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2023116822A1 (en) * 2021-12-23 2023-06-29 Beigene, Ltd. Solid forms of a tyk2 inhibitor, method of preparation, and use thereof
WO2023192351A1 (en) 2022-03-29 2023-10-05 Alumis Inc. Tyk2 inhibitors and uses thereof
WO2023220338A1 (en) * 2022-05-13 2023-11-16 Alumis Inc. Crystalline forms of a tyk2 inhibitor and uses thereof
WO2024059529A1 (en) * 2022-09-12 2024-03-21 Alumis Inc. Crystalline forms of a tyk2 inhibitor and uses thereof
WO2024081603A1 (en) * 2022-10-10 2024-04-18 Alumis Inc. Crystalline forms of a tyk2 inhibitor and uses thereof
WO2024102683A1 (en) * 2022-11-08 2024-05-16 Bristol-Myers Squibb Company Substituted heterocyclic compounds
US12006306B2 (en) 2021-04-28 2024-06-11 Alumis Inc. Substituted pyridazines as TYK2 inhibitors

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111484480B (zh) * 2019-01-29 2023-08-11 上海翰森生物医药科技有限公司 一种多环类衍生物抑制剂、其制备方法和应用
US20230150979A1 (en) * 2019-01-30 2023-05-18 Bristol-Myers Squibb Company Amide-disubstituted pyridine or pyridazine compounds
PE20220711A1 (es) 2019-09-27 2022-05-04 Takeda Pharmaceuticals Co Derivados de 2-isoindol-1,3,4-oxadiazol utiles como inhibidores de la histona desacetilasa 6 (hdac6)
CN113563309A (zh) * 2020-04-28 2021-10-29 浙江海正药业股份有限公司 吡啶类衍生物及其制备方法和用途
KR20230159421A (ko) 2021-02-19 2023-11-21 수도 바이오사이언시즈 리미티드 Tyk2 억제제 및 이의 용도
WO2023018694A1 (en) * 2021-08-10 2023-02-16 Revela, Inc. Compositions, formulations, and methods for hair treatment
WO2023109954A1 (en) * 2021-12-16 2023-06-22 Lynk Pharmaceuticals Co. Ltd. Tyk2 inhibitors and compositions and methods thereof
CN116693449A (zh) * 2022-03-04 2023-09-05 上海致根医药科技有限公司 用作tyk2抑制剂的化合物、其制备方法及其在医药上的应用
TW202348226A (zh) * 2022-06-07 2023-12-16 大陸商廣州費米子科技有限責任公司 噠嗪-3-甲醯胺化合物作為tyk2抑制劑

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058846A1 (ja) * 2008-11-21 2010-05-27 アステラス製薬株式会社 ４，６-ジアミノニコチンアミド化合物
WO2012061428A2 (en) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Nicotinamides as jak kinase modulators
WO2012061418A2 (en) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
WO2013104573A1 (en) * 2012-01-10 2013-07-18 F. Hoffmann-La Roche Ag Pyridazine amide compounds and their use as syk inhibitors
WO2015069310A1 (en) * 2013-11-07 2015-05-14 Bristol-Myers Squibb Company Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses
WO2015123453A1 (en) * 2014-02-14 2015-08-20 Portola Pharmaceuticals, Inc. Pyridazine compounds as jak inhibitors

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002228922A1 (en) 2000-12-12 2002-06-24 Cytovia, Inc. Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators of caspases and inducers of apoptosis and the use thereof
WO2004016597A2 (en) 2002-08-14 2004-02-26 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors and uses thereof
WO2006105222A2 (en) * 2005-03-25 2006-10-05 Scios Inc. Carboxamide inhibitors of tgfb
WO2009136995A2 (en) * 2008-04-16 2009-11-12 Portola Pharmaceuticals, Inc. Inhibitors of syk protein kinase
PL2428508T3 (pl) * 2009-05-08 2016-05-31 Astellas Pharma Inc Diaminoheterocykliczny związek karboksyamidowy
EP2918588B1 (en) 2010-05-20 2017-05-03 Array Biopharma, Inc. Macrocyclic compounds as TRK kinase inhibitors
CN102250065B (zh) 2011-05-20 2015-05-13 浙江海正药业股份有限公司 取代的三嗪苯脲衍生物及其用途
WO2013001310A1 (en) 2011-06-30 2013-01-03 Centro Nacional De Investigaciones Oncológicas (Cnio) Macrocyclic compounds and their use as cdk8 inhibitors
PL2760453T3 (pl) 2011-09-30 2016-11-30 Makrocykliczne Inhibitory kinazy LRRK2
HRP20220766T1 (hr) * 2012-11-08 2022-09-16 Bristol-Myers Squibb Company Amidom-supstituirani heterociklički spojevi korisni kao modulatori il-12, il-23 i/ili ifn alfa odgovora
CA2893115A1 (en) 2012-11-30 2014-06-05 Kyowa Hakko Kirin Co., Ltd. Nitrogen-containing heterocyclic compound
KR20150133765A (ko) 2013-03-15 2015-11-30 온코디자인 에스.에이. 거대고리 rip2 키나제 억제제
US10059663B2 (en) * 2013-08-29 2018-08-28 Kyoto Pharmaceutical Industries, Ltd. Aromatic compound and use thereof
KR20160093675A (ko) * 2013-12-05 2016-08-08 파마싸이클릭스 엘엘씨 브루톤 티로신 키나제의 억제제
ES2735729T3 (es) 2014-01-24 2019-12-20 Turning Point Therapeutics Inc Macrociclos de diarilo como moduladores de proteínas cinasas
CN105111151B (zh) 2015-04-17 2018-09-28 成都理工大学 作为PPAR-γ调节剂的氨基嘧啶衍生物
US20180305348A1 (en) * 2015-06-02 2018-10-25 Pharmacyclics Llc Inhibitors of brutons tyrosine kinase
US10316044B2 (en) 2015-07-02 2019-06-11 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
BR112018000297A2 (pt) 2015-07-06 2018-09-04 Tp Therapeutics Inc polimorfo de macrociclo de diarila
BR112018001065A2 (pt) 2015-07-21 2018-09-11 Tp Therapeutics, Inc. macrociclos diarila quirais e usos dos mesmos
BR112018008357A2 (pt) 2015-10-26 2018-11-27 Array Biopharma Inc mutações de ponto em câncer resistente a inibidor de trk e métodos relacionados às mesmas
WO2017087590A1 (en) 2015-11-18 2017-05-26 Bristol-Myers Squibb Company Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
ES2776658T3 (es) 2016-01-22 2020-07-31 Janssen Pharmaceutica Nv Nuevos derivados de cianoindolina con sustituyente heteroaromático de 6 miembros como inhibidores de NIK
MX2019001125A (es) 2016-07-28 2019-06-12 Tp Therapeutics Inc Inhibidores de cinasa macrociclica.
CN110036015B (zh) 2016-10-07 2022-07-19 百时美施贵宝公司 可用作IL-12、IL-23和/或IFNα应答的调节剂的咪唑并哒嗪化合物
JOP20190092A1 (ar) 2016-10-26 2019-04-25 Array Biopharma Inc عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
US11384150B2 (en) 2016-12-14 2022-07-12 Development Center For Biotechnology Antibody-drug conjugates and uses thereof
TWI808958B (zh) 2017-01-25 2023-07-21 美商特普醫葯公司 涉及二芳基巨環化合物之組合療法
CN106866660B (zh) 2017-02-15 2019-05-17 上海天马有机发光显示技术有限公司 电子传输材料、包含其的oled显示面板和电子设备
AU2018230737B2 (en) * 2017-03-08 2022-09-22 Takeda Pharmaceutical Company Limited Tyk2 inhibitors, uses, and methods for production thereof
JOP20190213A1 (ar) 2017-03-16 2019-09-16 Array Biopharma Inc مركبات حلقية ضخمة كمثبطات لكيناز ros1
CA3058880A1 (en) 2017-04-03 2018-10-11 Kyoto Pharmaceutical Industries, Ltd. Novel cyclin-dependent kinase 8 and/or 19 inhibitor
CN111094292A (zh) 2017-06-21 2020-05-01 豪夫迈·罗氏有限公司 作为IRAK4调节剂的吡唑并[1,5a]嘧啶衍生物
BR112020001695A2 (pt) 2017-07-28 2020-07-21 Turning Point Therapeutics, Inc. compostos macrocíclicos e usos dos mesmos
US10180422B1 (en) 2017-08-22 2019-01-15 Scripps Health Methods of treating a neuroendocrine tumor
WO2019037761A1 (zh) 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途
WO2019049891A1 (ja) 2017-09-06 2019-03-14 小野薬品工業株式会社 Ｔｒｋ阻害剤とキナーゼ阻害剤の併用による癌治療方法
WO2019084285A1 (en) 2017-10-26 2019-05-02 Qian Zhao FORMULATIONS OF A MACROCYCLIC TRK KINASE INHIBITOR
CN111556747B (zh) 2017-10-27 2023-11-17 索尼克马斯特有限公司 用于调节肌肉功能的dux4诱导的抑制剂
EP3706749B1 (en) 2017-11-10 2024-03-13 Angex Pharmaceutical, Inc. Macrocyclic compounds as trk kinase inhibitors and uses thereof
ES2929467T3 (es) 2017-12-19 2022-11-29 Turning Point Therapeutics Inc Compuestos macrocíclicos para tratar enfermedades
WO2019144885A1 (zh) 2018-01-23 2019-08-01 深圳市塔吉瑞生物医药有限公司 取代的吡唑并[1,5-a]嘧啶类的大环化合物
US11464780B2 (en) 2018-02-28 2022-10-11 Simcere Pharmaceutical Co. Ltd. Pyrazolopyrimidine derivative and use thereof
EP3773725A1 (en) 2018-03-29 2021-02-17 Loxo Oncology Inc. Treatment of trk-associated cancers
CN113490664A (zh) 2018-10-22 2021-10-08 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
JP2022518505A (ja) 2019-01-23 2022-03-15 ニンバス ラクシュミ， インコーポレイテッド Ｔｙｋ２阻害剤およびその使用
CN115448910B (zh) 2019-01-28 2024-04-19 江苏豪森药业集团有限公司 一种哒嗪类衍生物抑制剂、其制备方法和应用
AU2020218267A1 (en) 2019-02-07 2021-09-30 Ventyx Biosciences, Inc. TYK2 pseudokinase ligands
CN113811534A (zh) 2019-03-11 2021-12-17 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
MX2021011723A (es) 2019-03-26 2021-10-22 Ventyx Biosciences Inc Ligandos de pseudocinasa tyk2.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058846A1 (ja) * 2008-11-21 2010-05-27 アステラス製薬株式会社 ４，６-ジアミノニコチンアミド化合物
WO2012061428A2 (en) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Nicotinamides as jak kinase modulators
WO2012061418A2 (en) * 2010-11-01 2012-05-10 Portola Pharmaceuticals, Inc. Benzamides and nicotinamides as syk modulators
WO2013104573A1 (en) * 2012-01-10 2013-07-18 F. Hoffmann-La Roche Ag Pyridazine amide compounds and their use as syk inhibitors
WO2015069310A1 (en) * 2013-11-07 2015-05-14 Bristol-Myers Squibb Company Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifnalpha responses
WO2015123453A1 (en) * 2014-02-14 2015-08-20 Portola Pharmaceuticals, Inc. Pyridazine compounds as jak inhibitors

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"Organic Reactions", 1942, JOHN WILEY & SONS
"Remington: The Science and Practice of Pharmacy", 2005, MACK PUB. CO.
FUHRHOP, J.PENZLIN G.: "Organic Synthesis: Concepts, Methods, Starting Materials", 1994, JOHN WILEY & SONS
GREG COFFEY, FRANCIS DEGUZMAN, MAYUKO INAGAKI, YVONNE PAK, SUZANNE M. DELANEY, DAN IVES, ANDREAS BETZ, ZHAOZHONG J. JIA, ANJALI PA: "Specific Inhibition of Spleen Tyrosine Kinase Suppresses Leukocyte Immune Function and Inflammation in Animal Models of Rheumatoid Arthritis", JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, US, vol. 340, no. 2, 1 February 2012 (2012-02-01), US, pages 350 - 359, XP055707695, ISSN: 0022-3565, DOI: 10.1124/jpet.111.188441 *
H. O. HOUSE: "Modem Synthetic Reactions", 1972, W. A. BENJAMIN, INC. MENLO PARK
HOFFMAN, R.V.: "Organic Chemistry, An Intermediate Text", 1996, OXFORD UNIVERSITY PRESS
LAROCK, R. C.: "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia", 1999, JOHN WILEY & SONS
P. H. STAHLC. G. WERMUTH: "Handbook of Pharmaceutical Salts", 2002, VERLAG HELVETICA CHIMICA ACTA
S. R. SANDLER ET AL.: "Organic Functional Group Preparations", 1983, JOHN WILEY & SONS, INC.
See also references of EP3870579A4
SHILIN XU, LIANWEN ZHANG, SHAOHUA CHANG, JINFENG LUO, XIAOYUN LU, ZHENGCHAO TU, YINGXUE LIU, ZHANG ZHANG, YONG XU, XIAOMEI REN, KE: "Design, synthesis and biological evaluation of new molecules inhibiting epidermal growth factor receptor threonine790→ methionine790 mutant", MEDCHEMCOMM, vol. 3, no. 9, 1 January 2012 (2012-01-01), pages 1155, XP055096883, ISSN: 20402503, DOI: 10.1039/c2md20078c *
SOLOMONS, T. W. G.: "Modern Carbonyl Chemistry", 2000, JOHN WILEY & SONS
STOWELL, J.C.: "Intermediate Organic Chemistry", 1993, WILEY-INTERSCIENCE
T. L. GILCHRIST: "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 1992, WILEY-INTERSCIENCE

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11731956B2 (en) 2018-10-22 2023-08-22 Alumis Inc. Substituted 1,2,4-triazoles as intermediates in the synthesis of TYK2 inhibitors
US11053219B2 (en) 2018-10-22 2021-07-06 Esker Therapeutics, Inc. Substituted pyridines as TYK2 inhibitors
WO2021011513A1 (en) * 2019-07-16 2021-01-21 Bristol-Myers Squibb Company Prodrugs in the modulation of interleukin
CN114364665A (zh) * 2019-07-16 2022-04-15 百时美施贵宝公司 调节白介素的前药
WO2021180072A1 (en) * 2020-03-11 2021-09-16 Beijing Innocare Pharma Tech Co., Ltd. Heterocyclic compounds for inhibiting tyk2 activities
CN114650990A (zh) * 2020-03-11 2022-06-21 北京诺诚健华医药科技有限公司 抑制tyk2活性的杂环类化合物
US11578058B2 (en) 2020-03-11 2023-02-14 Beijing Innocare Pharma Tech Co. Heterocyclic compounds for inhibiting TYK2 activities
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WO2021202652A1 (en) * 2020-04-01 2021-10-07 Eternity Bioscience Inc. Tyrosine kinase 2 inhibitors, preparation methods and medicinal uses thereof
WO2021211741A1 (en) * 2020-04-14 2021-10-21 Gossamer Bio Services, Inc. Substituted pyridines for the treatment of inflammatory diseases
CN113735837A (zh) * 2020-05-28 2021-12-03 江苏先声药业有限公司 哒嗪类化合物及其用途
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CN113773262A (zh) * 2020-06-09 2021-12-10 江苏先声药业有限公司 哒嗪类化合物
WO2021259208A1 (en) * 2020-06-22 2021-12-30 Beigene, Ltd. Tyk-2 inhibitor
WO2022032484A1 (zh) * 2020-08-11 2022-02-17 北京诺诚健华医药科技有限公司 哒嗪-3-甲酰胺类化合物、其制备方法及其在医药学上的应用
WO2022033544A1 (zh) * 2020-08-13 2022-02-17 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2022105771A1 (zh) * 2020-11-17 2022-05-27 江苏恒瑞医药股份有限公司 含氮杂环类衍生物、其制备方法及其在医药上的应用
WO2022117016A1 (zh) * 2020-12-02 2022-06-09 深圳微芯生物科技股份有限公司 羟肟酸酯化合物、其制备方法及其应用
WO2022121868A1 (zh) * 2020-12-08 2022-06-16 正大天晴药业集团股份有限公司 含酰胺基和杂环烷基的tyk2抑制剂化合物
CN114981262A (zh) * 2020-12-22 2022-08-30 益方生物科技(上海)股份有限公司 杂芳基化合物及其制备方法和用途
WO2022135430A1 (en) * 2020-12-22 2022-06-30 InventisBio Co., Ltd. Heteroaryl compounds, preparation methods and uses thereof
WO2022179578A1 (zh) * 2021-02-24 2022-09-01 南京明德新药研发有限公司 含有亚磺酰基吡啶结构的化合物以及应用
CN112920103A (zh) * 2021-03-02 2021-06-08 康化（上海）新药研发有限公司 一种温和制备2-氮杂螺[3.3]庚烷盐酸盐的方法
WO2022193499A1 (en) * 2021-03-16 2022-09-22 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Amino heteroaryl compounds and compositions
CN117083268A (zh) * 2021-03-16 2023-11-17 安锐生物医药科技(广州)有限公司 氨基杂芳基化合物和组合物
CN115197196A (zh) * 2021-04-06 2022-10-18 扬子江药业集团有限公司 Tyk2抑制剂及其用途
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US12006306B2 (en) 2021-04-28 2024-06-11 Alumis Inc. Substituted pyridazines as TYK2 inhibitors
WO2022233286A1 (zh) * 2021-05-04 2022-11-10 上海喆邺生物科技有限公司 一类含氮杂环吡啶类化合物
US11884650B2 (en) 2021-05-14 2024-01-30 Bristol-Myers Squibb Company Substituted heterocyclic compounds
US20220388987A1 (en) * 2021-05-14 2022-12-08 Bristol-Myers Squibb Company Substituted heterocyclic compounds
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WO2023030335A1 (zh) * 2021-08-31 2023-03-09 浙江文达医药科技有限公司 作为tyk2/jak1假激酶结构域抑制剂的化合物及合成和使用方法
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WO2023054549A1 (ja) * 2021-09-30 2023-04-06 あすか製薬株式会社 分解誘導剤
WO2023064223A1 (en) * 2021-10-11 2023-04-20 Gossamer Bio Services, Inc. Tri-substituted pyridines
WO2023076161A1 (en) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Tyk2 degraders and uses thereof
WO2023116822A1 (en) * 2021-12-23 2023-06-29 Beigene, Ltd. Solid forms of a tyk2 inhibitor, method of preparation, and use thereof
WO2023116748A1 (zh) * 2021-12-23 2023-06-29 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
WO2023192351A1 (en) 2022-03-29 2023-10-05 Alumis Inc. Tyk2 inhibitors and uses thereof
WO2023220338A1 (en) * 2022-05-13 2023-11-16 Alumis Inc. Crystalline forms of a tyk2 inhibitor and uses thereof
WO2024059529A1 (en) * 2022-09-12 2024-03-21 Alumis Inc. Crystalline forms of a tyk2 inhibitor and uses thereof
WO2024081603A1 (en) * 2022-10-10 2024-04-18 Alumis Inc. Crystalline forms of a tyk2 inhibitor and uses thereof
WO2024102683A1 (en) * 2022-11-08 2024-05-16 Bristol-Myers Squibb Company Substituted heterocyclic compounds
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